Summary: Periodontitis is a common and serious dental disease in which billions of people suffer. It not only causes irreversible alveolar bone-loss but also is associated with systemic diseases such as atherosclerosis, diabetes and rheumatoid arthritis. Periodontitis has been characterized as an inflammatory disease associated with the interaction between the oral microbiota and host immune system. Both the innate and adaptive components of up ?60% the immune system are involved in the pathogenesis of periodontitis. As one of the key components of the adaptive immune system, B-lineage cells (B lymphocytes and plasma cells) make of the total leukocytes present in periodontal lesions and participate in the induction of pathological bone loss in chronic periodontitis. IL-37, a newly identified anti-inflammatory cytokine, indicated to associate with the severity of periodontitis by our genome-wide association study (GWAS). Furthermore, our preliminary studies found that IL-37b is the dominant isoform of IL-37 and highly expressed by plasma cells in the gingival tissue from periodontitis patients. These findings suggested strong correlation between IL-37b and plasma cells in periodontitis. However, the relationship among anti-inflammatory IL-37b, plasma cells and periodontitis remains completely unknown. The goal of this proposal is to gain a better understanding of the role of IL-37b from plasma cells in periodontitis progression. We propose three Specific Aims to explore the underlying mechanisms of the relationship among IL-37b, plasma cells and periodontitis in this study. (Aim 1): Investigate the role of IL-37b from plasma cells to regulate autologous RANKL production in periodontitis development. (Aim2): Investigate the role of IL-37b from plasma cells to suppress the differentiation of pre- osteoclasts into osteoclasts during periodontitis progression. (Aim3): Investigate the role of genetic variants of IL-37b from plasma cells during the progression of periodontitis. Considering the board anti-inflammatory activity, fully elucidating the mechanisms by which IL-37b regulates the pathogenesis of periodontists may highlight a new therapeutic approach for periodontal disease.